1-s2.0-S0022283617304448-main.pdf (2.26 MB)
Alzheimer's disease-like paired helical filament assembly from truncated tau protein is independent of disulphide cross-linking
journal contribution
posted on 2023-06-09, 07:58 authored by Youssra Al-Hilaly, Saskia Pollack, Devkee Vadukul, Francesca Citossi, Janet E Rickard, Michael Simpson, John M D Storey, Charles R Harrington, Claude M Wischik, Louise SerpellLouise SerpellAbstract Alzheimer's disease is characterised by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into {PHFs} is not well understood. Here we report that a truncated 95-amino acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process. Using electron microscopy, circular dichroism and X-ray fibre diffraction, we have characterised the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulphide formation to fibril formation, we have compared the assembly of tau(297-391) under reduced and non-reducing conditions and for truncated tau carrying a {C322A} substitution. We show that disulphide bond formation inhibits assembly and that the {C322A} variant rapidly forms long and highly ordered PHFs.
History
Publication status
- Published
File Version
- Published version
Journal
Journal of Molecular BiologyISSN
0022-2836Publisher
ElsevierExternal DOI
Issue
4Volume
429Page range
3650-3665Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes